RESUMEN
Static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WD repeat domain phosphoinositide interacting protein 4. However, the pathophysiology of the disease, particularly the function of WDR45/WD repeat domain phosphoinositide interacting protein 4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WD repeat domain phosphoinositide interacting protein 4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e. ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron-containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood/ß-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications.
RESUMEN
Tsukida K, Goto M, Yamaguchi N, Imagawa T, Tamura D, Yamagata T. Rotavirus gastroenteritis-associated urinary tract calculus in an infant. Turk J Pediatr 2018; 60: 769-770. Rotavirus gastroenteritis a severe viral gastroenteritis that occasionally causes post-renal failure with urinary tract calculus. A 15-month-old boy with rotavirus gastroenteritis suffered from pre- and post-renal dysfunction due to dehydration and urinary obstruction, respectively. Careful evaluations using abdominal ultrasound and cautious fluid replacement with urine alkalization led to an improvement in the pre- and post-renal dysfunction.
RESUMEN
INTRODUCTION: The relevant literature includes several case reports on cerebral infarction in children with HHV-6 infection; however, there is no report of brain stem infarction. CASE: An 11-month-old girl was hospitalized because of fever. She was unable to stand up and meet her mother's gaze. Magnetic resonance imaging (MRI) indicated a right pons and mid-brain lesion; a diagnosis of brainstem infarction was made. After her fever subsided, a rash developed on her trunk and limbs; blood examination results indicated a primary HHV-6 infection. She was treated with aspirin, edaravone, and mannitol to prevent further complications. At the age of 18months, the auditory brainstem response (ABR) was unremarkable and she is developing well. DISCUSSION AND CONCLUSION: A limited number of studies have reported HHV-6 infection-associated infarction, and no cases of brainstem infarction have been reported. One possible cause of cerebral infarction is antiphospholipid antibody syndrome (APS) triggered by the infection. HHV-6 may also directly infect vascular endothelial cells and cause angiopathy. However, the real mechanism of infarction remains unclear. Our patient had a favorable prognosis despite brainstem infarction.